The mechanism of bone loss is not well understood, but in practical effect, the disorder arises from an imbalance in the formation of new healthy bone and the resorption of old bone, with the result being a net loss of bone tissue. This bone loss includes a decrease in both mineral content and protein matrix components of the bone, and leads to an increased fracture rate of, predominantly, femoral bones and bones in the forearm and vertebrae. These fractures, in turn, lead to an increase in general morbidity, a marked loss of stature and mobility, and, in many cases, an increase in mortality resulting from complications.
Bone loss occurs in a wide range of subjects including aging men and women, post-menopausal women, patients who have undergone hysterectomy, patients who are undergoing or have undergone long-term administration of corticosteroids, patients suffering from Cushing's syndrome, and patents having gonadal dysgenesis.
Unchecked, bone loss can lead to osteoporosis and/or osteopenia. Osteopenia is reduced bone mass due to a decrease in the rate of osteoid synthesis to a level insufficient to compensate normal bone lysis. Osteoporosis is a major debilitating disease whose prominent feature is the loss of bone mass (decreased density and enlargement of bone spaces) without a reduction in bone volume, producing porosity and fragility.
One on the most common types of osteoporosis is found in post-menopausal women affecting an estimated 20 to 25 million women in the United States alone. A significant feature of post-menopausal osteoporosis is the large and rapid loss of bone mass due to the cessation of estrogen production by the ovaries. Indeed, estrogens have been shown to limit the progression of osteoporotic bone loss, and estrogen replacement is a recognized treatment for postmenopausal osteoporosis in the United States and many other countries. Although the administration of estrogens have beneficial effects on bone when given even at very low levels, long-term estrogen therapy has been implicated in a variety of disorders such as an increase in the risk of uterine and breast cancer, vaginal bleeding, and endometrial hyperplasia, causing many women to avoid this treatment. Recently suggested therapeutic regimens which seek to lessen the cancer risk, such as administering combinations of progestogen and estrogen, may be linked to negative cardiovascular effects. Concerns over the significant undesirable effects associated with estrogen therapy, and the limited ability of estrogens to reverse existing bone loss, support the need to develop alternative therapy for bone loss that generates the desirable effects on bone but does not cause undesirable effects.
Attempts to fill this need by the use of compounds commonly known as antiestrogens, which interact with the estrogen receptor, have had limited success, perhaps due to the fact that these compounds generally display a mixed agonist/antagonist effect. That is, although these compounds can antagonize estrogen interaction with the receptor, the compounds themselves may cause estrogenic responses in those tissues having estrogen receptors. Therefore, some antiestrogens, when administered alone, are subject to the same adverse effects associated with estrogen therapy.
Osteoporosis and osteopenia are present in both aging men and women, due to age-related bone loss.
Other treatments used for osteoporosis include vitamin and mineral supplementation with calcium and vitamin D. This has limited effectiveness in treating advanced disease and regular disease. The effectiveness of this treatment is limited in treating and preventing bone loss.
Treatment with bisphosphonates such as alendronate, currently marketed by Merck & Co., Inc. as FOSAMAX.RTM., has also been successfuil in inhibiting bone loss and increasing bone density. Bisphosphonates have low bioavailability and their administration must avoid food interactions. Treatment with shots or intranasal Calcitonin and low dose PTH (parathyroid horomone) shots have also been employed in an effort to inhibit bone loss and treat or prevent osteoporosis. Treatment with calcitonin is associated with a high rate of allergic reaction.
Treatments used for bone loss in men include vitamin and mineral supplementation with calcium and vitamin D. This has limited effectiveness in treating advanced disease and regular disease. The effectiveness of this treatment is limited in treating and preventing bone loss.
Also, bone loss in men is treated with androgens such as testosterone. Treatment with testosterone can lead to baldness, acne, lowering of HDL cholesterol (the "good" cholesterol) and raising of LDL cholesteroal (the "bad" cholesterol), and it may be associated with an increased risk of prostate cancer and benign prostatic hyperplasia.
U.S. Pat. No. 5,550,134, issued Aug. 27, 1996, describes methods for inhibiting the loss of bone with benzoquinolin-3-ones known to be inhibitors of the enzyme 5.alpha.-reductase type 1.
The present invention relates to methods of inhibiting bone loss without the associated adverse effects of hormone replacement therapy, and thus, serves as an effective acceptable treatment for osteoporosis and osteopenia and other diseases where inhibiting bone loss may be beneficial, including: Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral. It has now been found that a 5.alpha.-reductase type 1 inhibitors of structural formula I: ##STR2## are useful for the inhibition of bone loss and the treatment of the associated clinical conditions. In particular, the present invention relates to the use of compounds of structural formula I for the inhibition of bone loss and the treatment and prevention of osteoporosis and osteopenia and other diseases where inhibiting bone loss may be beneficial, including: Paget's disease, malignant hypercalcemia, periodontal disease, joint loosening and metastatic bone disease, as well as reducing the risk of fractures, both vertebral and nonvertebral. The inhibition of bone loss contemplated by the present methods includes both medical therapeutic and/or prophylactic treatment, as appropriate.
The enzyme 5.alpha.-reductase catalyzes the reduction of testosterone (T) to the more potent androgen, 5.alpha.-dihydrotestosterone (dihydrotestosterone" or DHT), as shown below: ##STR3##
There are two isozymes of 5.alpha.-reductase in humans. Andersson, et al., Proc. Natl. Acad. Sci. USA, 87:3640-44 (1990); Andersson, et al., Nature, 354, 159-61 (1991). The isozymes, usually called Type 1 and Type 2, exhibit differences in their biochemical properties, genetics, and pharmacology. Both isozymes are now the subject of considerable research and it has been found one isozyme (type 1) predominates in he sebaceous glands of facial skin and skin tissue and that the other (type 2) predominates in the prostate.
Finasteride (17.beta.-(N-tert-butylcarbamoyl)-3-oxo-4-aza-5.alpha.-androst-1-en-3-one) as shown below, is a potent inhibitor of the human type 2 enzyme. ##STR4## Under the tradename PROSCAR.RTM., finasteride is known to be useful in the treatment of hyperandrogenic conditions, see e.g., U.S. Pat. No. 4,760,071. Finasteride is currently prescribed for the treatment of benign prostatic hyperplasia (BPH), a condition affecting to some degree the majority of men over age 55. Finasteride's usefulness in the treatment of androgenic alopecia and prostatic cancer is described in the following documents: EP 0 285 382, published Oct. 5, 1988, EP 0 285 383, published Oct. 5, 1988 and Canadian patents 1,302,277 and 1,302,276.